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Kenichi Inui - One of the best experts on this subject based on the ideXlab platform.
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Organic Cation transporter octs slc22 and mates slc47 in the human kidney
Aaps Journal, 2013Co-Authors: Hideyuki Motohashi, Kenichi InuiAbstract:In the kidney, human Organic Cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) are the major transporters for the secretion of Cationic drugs into the urine. In the human kidney, OCT2 mediates the uptake of drugs from the blood at the basolateral membrane of tubular epithelial cells, and MATE1 and MATE2-K secrete drugs from cells into the lumen of proximal tubules. However, the expression of these transporters depends on the species of the animal. In the rodent kidney, OCT1 and OCT2 are expressed at the basolateral membrane, and MATE1 localizes at the brush-border membrane. Together, these transporters recognize various compounds and have overlapping, but somewhat different, substrate specificities. OCTs and MATEs can transport important drugs, such as metformin and cisplatin. Therefore, functional variation in OCTs and MATEs, including genetic polymorphisms or inter-individual variation, may seriously affect the pharmacokinetics and/or pharmacodynamics of Cationic drugs. In this review, we summarize the recent findings and clinical importance of these transporters.
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Organic Cation transporter oct slc22a and h Organic Cation antiporter mate slc47a are key molecules for nephrotoxicity of platinum agents
Biochemical Pharmacology, 2011Co-Authors: Atsushi Yonezawa, Kenichi InuiAbstract:Platinum agents have been widely used in cancer chemotherapy for a long time. Cisplatin, carboplatin, oxaliplatin and nedaplatin have a common chemical structure consisting of platinum, carrier groups and leaving groups, and undergo the similar mechanism of cytotoxicity. However, each agent differs in its efficacy and adverse effects, although the molecular mechanism involved is unclear. Recently, it was reported that Organic Cation transporter OCT/SLC22A, and multidrug and toxin extrusion MATE/SLC47A play a role in the pharmacokinetics of platinum agents. Only cisplatin induces nephrotoxicity and the toxicity is kidney-specific. Kidney-specific OCT2 mediates the transport of cisplatin and is the determinant of cisplatin-induced nephrotoxicity. In addition, cisplatin and oxaliplatin are substrates for these transporters, but carboplatin and nedaplatin are not. Substrate specificity could regulate the features of platinum agents. In this commentary, we will discuss the characteristics of OCT and MATE, and demonstrate the recent topics about the relationship between the transport of platinum agents by Organic Cation transporters and their pharmacological characteristics.
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physiological and pharmacokinetic roles of h Organic Cation antiporters mate slc47a
Biochemical Pharmacology, 2008Co-Authors: Tomohiro Terada, Kenichi InuiAbstract:Vectorial secretion of Cationic compounds across tubular epithelial cells is an important function of the kidney. This uni-directed transport is mediated by two cooperative functions, which are membrane potential-dependent Organic Cation transporters at the basolateral membranes and H+/Organic Cation antiporters at the brush-border membranes. More than 10 years ago, the basolateral Organic Cation transporters (OCT1-3/SLC22A1-3) were isolated, and molecular understandings for the basolateral entry of Cationic drugs have been greatly advanced. However, the molecular nature of H+/Organic Cation antiport systems remains unclear. Recently, mammalian orthologues of the multidrug and toxin extrusion (MATE) family of bacteria have been isolated and clarified to function as H+/Organic Cation antiporters. In this commentary, the molecular characteristics and pharmacokinetic roles of mammalian MATEs are critically overviewed focusing on the renal secretion of Cationic drugs.
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Physiological and pharmacokinetic roles of H+/Organic Cation antiporters (MATE/SLC47A).
Biochemical Pharmacology, 2007Co-Authors: Tomohiro Terada, Kenichi InuiAbstract:Vectorial secretion of Cationic compounds across tubular epithelial cells is an important function of the kidney. This uni-directed transport is mediated by two cooperative functions, which are membrane potential-dependent Organic Cation transporters at the basolateral membranes and H+/Organic Cation antiporters at the brush-border membranes. More than 10 years ago, the basolateral Organic Cation transporters (OCT1-3/SLC22A1-3) were isolated, and molecular understandings for the basolateral entry of Cationic drugs have been greatly advanced. However, the molecular nature of H+/Organic Cation antiport systems remains unclear. Recently, mammalian orthologues of the multidrug and toxin extrusion (MATE) family of bacteria have been isolated and clarified to function as H+/Organic Cation antiporters. In this commentary, the molecular characteristics and pharmacokinetic roles of mammalian MATEs are critically overviewed focusing on the renal secretion of Cationic drugs.
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cisplatin and oxaliplatin but not carboplatin and nedaplatin are substrates for human Organic Cation transporters slc22a1 3 and multidrug and toxin extrusion family
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: Atsushi Yonezawa, T Katsura, Satohiro Masuda, Sachiko Yokoo, Kenichi InuiAbstract:We have examined the role of the human Organic Cation transporters [hOCTs and human novel Organic Cation transporter (hOCTN); SLC22A1–5] and apical multidrug and toxin extrusion (hMATE) in the cellular accumulation and cytotoxicity of platinum agents using the human embryonic kidney (HEK) 293 cells transiently transfected with the transporter cDNAs. Both the cytotoxicity and accumulation of cisplatin were enhanced by the expression of hOCT2 and weakly by hOCT1, and those of oxaliplatin were also enhanced by the expression of hOCT2 and weakly by hOCT3. The hOCT-mediated uptake of tetraethylammonium (TEA) was markedly decreased in the presence of cisplatin in a concentration-dependent manner. However, oxaliplatin showed almost no influence on the TEA uptakes in the HEK293 cells expressing hOCT1, hOCT2, and hOCT3. The hMATE1 and hMATE2-K, but not hOCTN1 and OCTN2, mediated the cellular accumulation of cisplatin and oxaliplatin without a marked release of lactate dehydrogenase. Oxaliplatin, but not cisplatin, markedly decreased the hMATE2-K-mediated TEA uptake. However, the inhibitory effect of cisplatin and oxaliplatin against the hMATE1-mediated TEA uptake was similar. The release of lactate dehydrogenase and the cellular accumulation of carboplatin and nedaplatin were not found in the HEK293 cells transiently expressing these seven Organic Cation transporters. These results indicate that cisplatin is a relatively good substrate of hOCT1, hOCT2, and hMATE1, and oxaliplatin is of hOCT2, hOCT3, hMATE1, and hMATE2-K. These transporters could play predominant roles in the tissue distribution and anticancer effects and/or adverse effects of platinum agent-based chemotherapy.
Kathleen M Giacomini - One of the best experts on this subject based on the ideXlab platform.
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effect of genetic variation in the Organic Cation transporter 1 oct1 on metformin pharmacokinetics
Clinical Pharmacology & Therapeutics, 2008Co-Authors: Chaline Brown, Claire M Brett, Richard A Castro, Ryan P Owen, S A Sheardown, Esteban G Burchard, Kathleen M GiacominiAbstract:The goal of this study was to determine the effects of genetic variation in the Organic Cation transporter 1, OCT1, on the pharmacokinetics of the antidiabetic drug, metformin. Twenty healthy volunteers with known OCT1 genotype agreed to participate in the study. Each subject received two oral doses of metformin followed by collection of blood and urine samples. OCT1 genotypes had a significant (P<0.05) effect on metformin pharmacokinetics, with a higher area under the plasma concentration–time curve (AUC), higher maximal plasma concentration (Cmax), and lower oral volume of distribution (V/F) in the individuals carrying a reduced function OCT1 allele (R61C, G401S, 420del, or G465R). The effect of OCT1 on metformin pharmacokinetics in mice was less than in humans possibly reflecting species differences in hepatic expression level of the transporter. Our studies suggest that OCT1 genotype is a determinant of metformin pharmacokinetics.
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transporters involved in the elimination of drugs in the kidney Organic anion transporters and Organic Cation transporters
Journal of Pharmaceutical Sciences, 2001Co-Authors: Mark J. Dresser, Maya K Leabman, Kathleen M GiacominiAbstract:Abstract Transporters in the kidney mediate the secretion or reabsorption of many compounds and thereby influence the plasma levels of their substrates. Organic anion transporters and Organic Cation transporters are two major classes of secretory transporters in the mammalian kidney. During the past decade, significant progress has been made in the cloning, functional expression, and initial characterization of these transporters. To date, five Organic Cation transporters and nine Organic anion transporters have been cloned. In this review, we summarize the available data on Organic anion and Organic Cation transporters, focusing in particular on their molecular characteristics, tissue distribution, and inhibitor and substrate selectivities. Currently we have a good understanding of the inhibitor selectivities for most of these transporters, and with the development of more robust assays, we will soon have a better understanding of their substrate selectivities. Based on the available data, summarized in this review, it appears that many compounds interact with multiple transporters. Futhermore, there appears to be substantial overlap in the selectivities of Organic Cation transporters, and the same appears true for Organic anion transporters. At the present time, it is unclear what the roles of these multiple transporters are in renal drug elimination. With the development of new assays, reagents, and experimental methods, we will soon have a better understanding of the roles of each transporter isoform in the renal elimination of drugs. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:397–421, 2001
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Molecular and Functional Characteristics of Cloned Human Organic Cation Transporters
Pharmaceutical biotechnology, 1999Co-Authors: Mark J. Dresser, Lei Zhang, Kathleen M GiacominiAbstract:Within the last 5 years the Organic Cation transport field has moved from tissue and cellular levels to a molecular level of investigation. As we gain a better understanding of the genes and proteins responsible for the multiple mechanisms of Organic Cation transport, we can begin to apply this knowledge to pharmaceutical and drug discovery research. For example, in the future, we will know all of the transporters that are expressed in each tissue and have a substrate/inhibitor profile for each transporter. With this information, we could begin to predict, for example, organ-specific clearances or organ-specific distributions of drugs. Perhaps we will discover a brain-specific Organic Cation transporter which could serve as a drug target. It will be years and perhaps several more decades before all of these transporters are cloned and characterized. We have made a good start and there will be years of exciting work and discovery in the Organic Cation transport field in the future.
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Molecular cloning and functional expression of a rabbit renal Organic Cation transporter
Biochimica et Biophysica Acta, 1998Co-Authors: Shigeyuki Terashita, Lei Zhang, Mark J. Dresser, Andrew T Gray, Spencer C Yost, Kathleen M GiacominiAbstract:Abstract A cDNA encoding an Organic Cation transporter (rbOCT1) was isolated from rabbit kidney. The cDNA encodes a 554 amino acid protein that is highly homologous to other mammalian Organic Cation transporters. rbOCT1 mediated 3 H-1-methyl-4-phenylpyridinium ( 3 H-MPP + ) transport in Xenopus laebis oocytes was saturable, sensitive to membrane potential, and inhibited by various Organic Cations. rbOCT1 mRNA transcripts are expressed in the kidney, liver, and intestine.
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role of Organic Cation transporters in drug absorption and elimination
Annual Review of Pharmacology and Toxicology, 1998Co-Authors: Lei Zhang, Claire M Brett, Kathleen M GiacominiAbstract:▪ Abstract Organic Cation transporters are critical in drug absorption, targeting, and disposition. It has become increasingly clear that multiple mechanisms are involved in Organic Cation transport in the key tissues responsible for drug absorption and disposition: the kidney, liver, and intestine. In this review, we discuss current models of transepithelial flux of Organic Cations in these three tissues. Particular emphasis is placed on the more recent molecular studies that have paved the way for a more complete understanding of the physiological and pharmacological roles of the Organic Cation transporters. Such information is essential in predicting pharmacokinetics and pharmacodynamics and in the design and development of Cationic drugs.
Vadivel Ganapathy - One of the best experts on this subject based on the ideXlab platform.
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Mutations in novel Organic Cation transporter (OCTN2), an Organic Cation/carnitine transporter, with differential effects on the Organic Cation transport function and the carnitine transport function.
Journal of Biological Chemistry, 1999Co-Authors: Pankaj Seth, Xiang Wu, Wei Huang, Frederick H. Leibach, Vadivel GanapathyAbstract:Abstract Novel Organic Cation transporter (OCTN2) is an Organic Cation/carnitine transporter, and two missense mutations, L352R and P478L, in OCTN2 have been identified as the cause for primary carnitine deficiency. In the present study, we assessed the influence of these two mutations on the carnitine transport function and the Organic Cation transport function of OCTN2. The L352R mutation resulted in a complete loss of both transport functions. In contrast, the P478L mutation resulted in a complete loss of only the carnitine transport function but significantly stimulated the Organic Cation transport function. Studies with human OCTN2/rat OCTN2 chimeric transporters indicated that the carnitine transport site and the Organic Cation transport site were not identical. Because carnitine transport is Na+-dependent whereas Organic Cation transport is Na+-independent, we investigated the possibility that the P478L mutation affected Na+ binding. The Na+ activation kinetics were found to be similar for the P478L mutant and wild type OCTN2. We then mutated nine different tyrosine residues located in or near transmembrane domains and assessed the transport function of these mutants. One of these mutations, Y211F, was found to have differential influence on the two transport activities of OCTN2 as did the P478L mutation. However, the Na+ activation kinetics were not affected. These findings are of clinical relevance to patients with primary carnitine deficiency because whereas each and every mutation in these patients is expected to result in the loss of the carnitine transport function, all of these mutations may not interfere with the Organic Cation transport function.
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functional characteristics and tissue distribution pattern of Organic Cation transporter 2 octn2 an Organic Cation carnitine transporter
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Xiang Wu, Pankaj Seth, Wei Huang, Frederick H. Leibach, Puttur D Prasad, Deva P Rajan, Jinwen Chen, Simon J Conway, Vadivel GanapathyAbstract:We have demonstrated in the present study that novel Organic Cation transporter (OCTN) 2 is a transporter for Organic Cations as well as carnitine. OCTN2 transports Organic Cations without involving Na+, but it transports carnitine only in the presence of Na+. The ability to transport Organic Cations and carnitine is demonstrable with human, rat, and mouse OCTN2s. Na+ does not influence the affinity of OCTN2 for Organic Cations, but it increases the affinity severalfold for carnitine. The short-chain acyl esters of carnitine are also transported by OCTN2. Two mutations, M352R and P478L, in human OCTN2 are associated with loss of transport function, but the protein expression of these mutants is comparable to that of the wild-type human OCTN2. In situ hybridization in the rat shows that OCTN2 is expressed in the proximal and distal tubules and in the glomeruli in the kidney, in the myocardium, valves, and arterioles in the heart, in the labyrinthine layer of the placenta, and in the cortex, hippocampus, and cerebellum in the brain. This is the first report that OCTN2 is a Na+-independent Organic Cation transporter as well as a Na+-dependent carnitine transporter and that OCTN2 is expressed not only in the heart, kidney, and placenta but also in the brain.
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Functional Characteristics and Tissue Distribution Pattern of Organic Cation Transporter 2 (OCTN2), an Organic Cation/Carnitine Transporter
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Xiang Wu, Pankaj Seth, Wei Huang, Frederick H. Leibach, Puttur D Prasad, Deva P Rajan, Jinwen Chen, Simon J Conway, Vadivel GanapathyAbstract:We have demonstrated in the present study that novel Organic Cation transporter (OCTN) 2 is a transporter for Organic Cations as well as carnitine. OCTN2 transports Organic Cations without involving Na+, but it transports carnitine only in the presence of Na+. The ability to transport Organic Cations and carnitine is demonstrable with human, rat, and mouse OCTN2s. Na+ does not influence the affinity of OCTN2 for Organic Cations, but it increases the affinity severalfold for carnitine. The short-chain acyl esters of carnitine are also transported by OCTN2. Two mutations, M352R and P478L, in human OCTN2 are associated with loss of transport function, but the protein expression of these mutants is comparable to that of the wild-type human OCTN2. In situ hybridization in the rat shows that OCTN2 is expressed in the proximal and distal tubules and in the glomeruli in the kidney, in the myocardium, valves, and arterioles in the heart, in the labyrinthine layer of the placenta, and in the cortex, hippocampus, and cerebellum in the brain. This is the first report that OCTN2 is a Na+-independent Organic Cation transporter as well as a Na+-dependent carnitine transporter and that OCTN2 is expressed not only in the heart, kidney, and placenta but also in the brain.
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Identity of the F52F12.1 gene product in Caenorhabditis elegans as an Organic Cation transporter
Biochimica et Biophysica Acta, 1999Co-Authors: Xiang Wu, Wei Huang, Frederick H. Leibach, Christy Chancy, Vadivel GanapathyAbstract:Abstract We describe here the cloning and functional characterization of an Organic Cation transporter from Caenorhabditis elegans (CeOCT1). The CeOCT1 cDNA is 1826 bp long and codes for a protein of 568 amino acids. The oct1 gene is ∼3.2 kb in size and consists of 12 exons. The loCation of this gene corresponds to the F52F12.1 gene locus on chromosome I. The predicted protein contains 12 putative transmembrane domains. It exhibits significant homology to mammalian OCTs. When expressed in mammalian cells, CeOCT1 induces the transport of the prototypical Organic Cation tetraethylammonium. The Michaelis–Menten constant for this substrate is 80±16 μM. The substrate specificity of CeOCT1 is broad. This represents the first report on the cloning and functional characteristics of an Organic Cation transporter from C. elegans.
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mutations in the Organic Cation carnitine transporter octn2 in primary carnitine deficiency
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Yuhuan Wang, Vadivel Ganapathy, Jing Ye, Nicola LongoAbstract:Primary carnitine deficiency is an autosomal recessive disorder of fatty acid oxidation caused by defective carnitine transport. This disease presents early in life with hypoketotic hypoglycemia or later in life with skeletal myopathy or cardiomyopathy. The gene for this condition maps to 5q31.2–32 and OCTN2, an Organic Cation/carnitine transporter, also maps to the same chromosomal region. Here we test the causative role of OCTN2 in primary carnitine deficiency by searching for mutations in this gene in affected patients. Fibroblasts from patients with primary carnitine deficiency lacked mediated carnitine transport. Transfection of patient’s fibroblasts with the OCTN2 cDNA partially restored carnitine transport. Sequencing of the OCTN2 gene revealed different mutations in two unrelated patients. The first patient was homozygous (and both parents heterozygous) for a single base pair substitution converting the codon for Arg-282 to a STOP codon (R282X). The second patient was a compound heterozygote for a paternal 1-bp insertion producing a STOP codon (Y401X) and a maternal 1-bp deletion that produced a frameshift creating a subsequent STOP codon (458X). These mutations decreased the levels of mature OCTN2 mRNA and resulted in nonfunctional transporters, confirming that defects in the Organic Cation/carnitine transporter OCTN2 are responsible for primary carnitine deficiency.
Hermann Koepsell - One of the best experts on this subject based on the ideXlab platform.
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Regulation of the human Organic Cation transporter hOCT1
Journal of Cellular Physiology, 2020Co-Authors: Giuliano Ciarimboli, Hermann Koepsell, Valentin Gorboulev, Katja Struwe, Petra Arndt, Eberhard Schlatter, Jochen R. HirschAbstract:: The human Organic Cation transporter type 1 (hOCT1) is an important transport system for small Organic Cations in the liver. Organic Cation transporters are regulated by different signaling pathways, but the regulation of hOCT1 has not yet been studied. In this work, we have for the first time investigated the regulation of hOCT1. hOCT1 was expressed in Chinese hamster ovary cells (CHO-hOCT1) and in human embryonic kidney cells (HEK293-hOCT1). Its activity was monitored using microfluorimetry with the fluorescent Organic Cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP(+)) as substrate. hOCT1 expressed in CHO-cells was inhibited by protein kinase A (PKA) activation (1 microM forskolin, -58 +/- 6%, n = 12), calmodulin inhibition (0.1 microM calmidazolium, -68 +/- 3%, n = 6; 10 microM ophiobolin A, -48 +/- 10%, n = 7), calmodulin-dependent kinase II inhibition (1 microM KN62, -78 +/- 4%, n = 12), and inhibition of p56(lck) tyrosine kinase (10 microM aminogenistein, -35 +/- 7%, n = 12). The apparent affinities for TEA(+) were lower in CHO-hOCT1 than in HEK293-hOCT1, while those for TPA(+) and quinine were almost identical; the rank order of EC(50) values (TPA(+) > quinine > TEA(+)) was independent of the expression system. EC(50) values for TEA(+) in CHO-hOCT1 or HEK293-hOCT1 were increased under calmidazolium incubation (6.3 and 1.4 mM, respectively). hOCT1 was inhibited by PKA and endogenously activated by calmodulin, calmodulin-dependent kinase II, and p56(lck) tyrosine kinase. Regulation pathways were the same in the two expression systems. Since apparent substrate affinities depend on activity of regulatory pathways, the expression system plays a role in determining the substrate affinities.
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cisplatin nephrotoxicity is critically mediated via the human Organic Cation transporter 2
American Journal of Pathology, 2005Co-Authors: Giuliano Ciarimboli, Hermann Koepsell, Thomas Ludwig, Detlef Lang, Hermann Pavenstadt, Hansjurgen Piechota, Jorg Haier, Ulrich Jaehde, Jochen Zisowsky, Eberhard SchlatterAbstract:Cis- platin is an effective anti-neoplastic agent, but it is also highly nephrotoxic. Here, we clearly identify the human Organic Cation transporter 2 (hOCT2) as the critical transporter for cis- platin nephrotoxicity in isolated human proximal tubules and offer a potential mechanism for reducing nephrotoxicity in clinical practice. Interaction of cis- platin with hOCT2 in kidney or hOCT1 in liver was investigated with the fluorescent Cation 4-[4-(dimethyl-amino)styril]-methylpyridinium in stably transfected HEK293 cells and for the first time in tissues physiologically expressing these transporters, human proximal tubules, and human hepatocyte couplets. Cis- platin (100 μmol/L) inhibited transport via hOCT2-HEK293 but not hOCT1-HEK293. In human proximal tubules cis- platin competed with basolateral Organic Cation transport, whereas it had no effect in tubules from a diabetic kidney or in hepatocytes. In hOCT2-HEK293 cells treated for 15 hours, incubation with cis- platin induced apoptosis, which was completely suppressed by contemporaneous incubation with the hOCT2 substrate cimetidine (100 μmol/L). These findings demonstrate that uptake of cis- platin is mediated by hOCT2 in renal proximal tubules, explaining its organ-specific toxicity. A combination of cis- platin with other substrates that compete for hOCT2 offers an effective option to decrease nephrotoxicity in the clinical setting.
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polyspecific Organic Cation transporters their functions and interactions with drugs
Trends in Pharmacological Sciences, 2004Co-Authors: Hermann KoepsellAbstract:Abstract The body is equipped with broad-specificity transporters for the uptake, elimination and distribution of drugs, environmental toxins and metabolic waste products. The Organic Cation transporters [OCT1–OCT3 (also known as SLC22A1–SLC22A3)], which are expressed in the small intestine, liver, kidney, heart, placenta, lung and brain, facilitate the diffusion of structurally diverse Organic Cations including monoamine neurotransmitters and many drugs. These transporters contain substrate-binding pockets with partially overlapping binding domains for substrates and inhibitors. Recent studies in knockout mice show that OCT1 in the liver is involved in the hepatic uptake of Cationic drugs and, therefore, affects their net hepatobiliary excretion. In addition, OCT1 and OCT2 in renal proximal tubules participate in the secretion of Cationic drugs from the kidney. The recent identifiCation of polymorphisms in human OCTs enables the identifiCation of patients who have an increased risk of adverse drug reactions. Transport studies with expressed OCTs will help to optimize pharmacokinetic properties during the development of new drugs.
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Organic Cation transporters
Reviews of Physiology Biochemistry and Pharmacology, 2003Co-Authors: Hermann Koepsell, Bernhard M Schmitt, Valentin GorboulevAbstract:Over the last 15 years, a number of transporters that translocate Organic Cations were characterized functionally and also identified on the molecular level. Organic Cations include endogenous compounds such as monoamine neurotransmitters, choline, and coenzymes, but also numerous drugs and xenobiotics. Some of the cloned Organic Cation transporters accept one main substrate or structurally similar compounds (oligospecific transporters), while others translocate a variety of structurally diverse Organic Cations (polyspecific transporters). This review provides a survey of cloned Organic Cation transporters and tentative models that illustrate how different types of Organic Cation transporters, expressed at specific subcellular sites in hepatocytes and renal proximal tubular cells, are assembled into an integrated functional framework. We briefly describe oligospecific Na+- and Cl−-dependent monoamine neurotransmitter transporters (SLC6-family), high-affinity choline transporters (SLC5-family), and high-affinity thiamine transporters (SLC19-family), as well as polyspecific transporters that translocate some Organic Cations next to their preferred, nonCationic substrates. The polyspecific Cation transporters of the SLC22 family including the subtypes OCT1-3 and OCTN1-2 are presented in detail, covering the current knowledge about distribution, substrate specificity, and recent data on their electrical properties and regulation. Moreover, we discuss artificial and spontaneous mutations of transporters of the SLC22 family that provide novel insight as to the function of specific protein domains. Finally, we discuss the clinical potential of the increasing knowledge about polymorphisms and mutations in polyspecific Organic Cation transporters.
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identifiCation of genetic variations of the human Organic Cation transporter hoct1 and their functional consequences
Pharmacogenetics, 2002Co-Authors: Reinhold Kerb, Valentin Gorboulev, Ulrich Brinkmann, Natalia Chatskaia, Dmitry Gorbunov, Esther Mornhinweg, Andrea Keil, Michel Eichelbaum, Hermann KoepsellAbstract:By systematic mutation screening of the polyspecific Organic Cation transporter hOCT1 (SLC22A1) in 57 Caucasians, 25 genetic variations were identified and further analysed for population frequency. Five mutations resulting in the amino acid changes Arg61Cys, Cys88Arg, Phe160Leu, Gly401Ser, and Met4
Xiang Wu - One of the best experts on this subject based on the ideXlab platform.
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Mutations in novel Organic Cation transporter (OCTN2), an Organic Cation/carnitine transporter, with differential effects on the Organic Cation transport function and the carnitine transport function.
Journal of Biological Chemistry, 1999Co-Authors: Pankaj Seth, Xiang Wu, Wei Huang, Frederick H. Leibach, Vadivel GanapathyAbstract:Abstract Novel Organic Cation transporter (OCTN2) is an Organic Cation/carnitine transporter, and two missense mutations, L352R and P478L, in OCTN2 have been identified as the cause for primary carnitine deficiency. In the present study, we assessed the influence of these two mutations on the carnitine transport function and the Organic Cation transport function of OCTN2. The L352R mutation resulted in a complete loss of both transport functions. In contrast, the P478L mutation resulted in a complete loss of only the carnitine transport function but significantly stimulated the Organic Cation transport function. Studies with human OCTN2/rat OCTN2 chimeric transporters indicated that the carnitine transport site and the Organic Cation transport site were not identical. Because carnitine transport is Na+-dependent whereas Organic Cation transport is Na+-independent, we investigated the possibility that the P478L mutation affected Na+ binding. The Na+ activation kinetics were found to be similar for the P478L mutant and wild type OCTN2. We then mutated nine different tyrosine residues located in or near transmembrane domains and assessed the transport function of these mutants. One of these mutations, Y211F, was found to have differential influence on the two transport activities of OCTN2 as did the P478L mutation. However, the Na+ activation kinetics were not affected. These findings are of clinical relevance to patients with primary carnitine deficiency because whereas each and every mutation in these patients is expected to result in the loss of the carnitine transport function, all of these mutations may not interfere with the Organic Cation transport function.
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functional characteristics and tissue distribution pattern of Organic Cation transporter 2 octn2 an Organic Cation carnitine transporter
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Xiang Wu, Pankaj Seth, Wei Huang, Frederick H. Leibach, Puttur D Prasad, Deva P Rajan, Jinwen Chen, Simon J Conway, Vadivel GanapathyAbstract:We have demonstrated in the present study that novel Organic Cation transporter (OCTN) 2 is a transporter for Organic Cations as well as carnitine. OCTN2 transports Organic Cations without involving Na+, but it transports carnitine only in the presence of Na+. The ability to transport Organic Cations and carnitine is demonstrable with human, rat, and mouse OCTN2s. Na+ does not influence the affinity of OCTN2 for Organic Cations, but it increases the affinity severalfold for carnitine. The short-chain acyl esters of carnitine are also transported by OCTN2. Two mutations, M352R and P478L, in human OCTN2 are associated with loss of transport function, but the protein expression of these mutants is comparable to that of the wild-type human OCTN2. In situ hybridization in the rat shows that OCTN2 is expressed in the proximal and distal tubules and in the glomeruli in the kidney, in the myocardium, valves, and arterioles in the heart, in the labyrinthine layer of the placenta, and in the cortex, hippocampus, and cerebellum in the brain. This is the first report that OCTN2 is a Na+-independent Organic Cation transporter as well as a Na+-dependent carnitine transporter and that OCTN2 is expressed not only in the heart, kidney, and placenta but also in the brain.
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Functional Characteristics and Tissue Distribution Pattern of Organic Cation Transporter 2 (OCTN2), an Organic Cation/Carnitine Transporter
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Xiang Wu, Pankaj Seth, Wei Huang, Frederick H. Leibach, Puttur D Prasad, Deva P Rajan, Jinwen Chen, Simon J Conway, Vadivel GanapathyAbstract:We have demonstrated in the present study that novel Organic Cation transporter (OCTN) 2 is a transporter for Organic Cations as well as carnitine. OCTN2 transports Organic Cations without involving Na+, but it transports carnitine only in the presence of Na+. The ability to transport Organic Cations and carnitine is demonstrable with human, rat, and mouse OCTN2s. Na+ does not influence the affinity of OCTN2 for Organic Cations, but it increases the affinity severalfold for carnitine. The short-chain acyl esters of carnitine are also transported by OCTN2. Two mutations, M352R and P478L, in human OCTN2 are associated with loss of transport function, but the protein expression of these mutants is comparable to that of the wild-type human OCTN2. In situ hybridization in the rat shows that OCTN2 is expressed in the proximal and distal tubules and in the glomeruli in the kidney, in the myocardium, valves, and arterioles in the heart, in the labyrinthine layer of the placenta, and in the cortex, hippocampus, and cerebellum in the brain. This is the first report that OCTN2 is a Na+-independent Organic Cation transporter as well as a Na+-dependent carnitine transporter and that OCTN2 is expressed not only in the heart, kidney, and placenta but also in the brain.
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Identity of the F52F12.1 gene product in Caenorhabditis elegans as an Organic Cation transporter
Biochimica et Biophysica Acta, 1999Co-Authors: Xiang Wu, Wei Huang, Frederick H. Leibach, Christy Chancy, Vadivel GanapathyAbstract:Abstract We describe here the cloning and functional characterization of an Organic Cation transporter from Caenorhabditis elegans (CeOCT1). The CeOCT1 cDNA is 1826 bp long and codes for a protein of 568 amino acids. The oct1 gene is ∼3.2 kb in size and consists of 12 exons. The loCation of this gene corresponds to the F52F12.1 gene locus on chromosome I. The predicted protein contains 12 putative transmembrane domains. It exhibits significant homology to mammalian OCTs. When expressed in mammalian cells, CeOCT1 induces the transport of the prototypical Organic Cation tetraethylammonium. The Michaelis–Menten constant for this substrate is 80±16 μM. The substrate specificity of CeOCT1 is broad. This represents the first report on the cloning and functional characteristics of an Organic Cation transporter from C. elegans.
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cloning and functional characterization of a potential sensitive polyspecific Organic Cation transporter oct3 most abundantly expressed in placenta
Journal of Biological Chemistry, 1998Co-Authors: Ramesh Kekuda, Xiang Wu, Frederick H. Leibach, Puttur D Prasad, Haiping Wang, Vadivel GanapathyAbstract:Abstract We have isolated a cDNA from rat placenta which, when expressed heterologously, mediates the transport of a wide spectrum of Organic Cations. The cDNA codes for a protein of 551 amino acids containing 12 putative transmembrane domains. Northern blot analysis indicates that this transporter is expressed most abundantly in the placenta and moderately in the intestine, heart, and brain. The expression is comparatively low in the kidney and lung and is undetectable in the liver. This transporter is distinct from the previously cloned Organic Cation transporters (OCT1, OCT2, NKT, NLT, RST, and OCTN1). When expressed in HeLa cells, the cDNA induces the transport of tetraethylammonium and guanidine. Competition experiments indicate that this transport process recognizes a large number of Organic Cations, including the neurotoxin 1-methyl-4-phenylpyridinium, as substrates. The cDNA-induced transport is markedly influenced by extracellular pH. However, when expressed in Xenopus laevisoocytes, the cDNA-induced transport is electrogenic, associated with the transfer of positive charge into the oocytes. Under voltage clamp conditions, tetraethylammonium evokes inward currents that are concentration- and potential-dependent. This potential-sensitive Organic Cation transporter, designated as OCT3, represents a new member of the OCT gene family.